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P Benatti

Publications and source records attributed to P Benatti.

At least 19 recordsLinked to original sources
PubMed2006

A genetic model for determining MSH2 and MLH1 carrier probabilities based on family history and tumor microsatellite instability.

Mutation-predicting models can be useful when deciding on the genetic testing of individuals at risk and in determining the cost effectiveness of screening strategies at the population level. The aim of this study was to evaluate the performance of a newly developed genetic model that incorporates tumor microsatellite instability (MSI) information, called the AIFEG model, and in predicting the presence of mutations in MSH2 and MLH1 in probands with suspected hereditary non-polyposis colorectal cancer. The AIFEG model is based on published estimates of mutation frequencies and cancer penetrances in carriers and non-carriers and employs the program MLINK of the FASTLINK package to calculate the proband's carrier probability. Model performance is evaluated in a series of 219 families screened for mutations in both MSH2 and MLH1, in which 68 disease-causing mutations were identified. Predictions are first obtained using family history only and then converted into posterior probabilities using information on MSI. This improves predictions substantially. Using a probability threshold of 10% for mutation analysis, the AIFEG model applied to our series has 100% sensitivity and 71% specificity.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Different phenotypes in Muir-Torre syndrome: clinical and biomolecular characterization in two Italian families.

The Muir-Torre syndrome (MTS) is an autosomal dominant genodermatosis characterized by the presence of sebaceous gland tumours, with or without keratoacanthomas, associated with visceral malignancies. We describe and characterize two families in which the ample phenotypic variability of MTS was evident. After clinical evaluation, the skin and visceral tumours of one member of a family with 'classic' MTS and one member of a family with a 'peculiar' MTS phenotype without sebaceous lesions, but with only multiple keratoacanthomas, were analysed for microsatellite instability (MSI) and by immunohistochemistry. Tumours of both individuals showed MSI, with a concomitant lack of MSH2 immunostaining in all evaluated skin and visceral lesions; moreover, in the proband of family 2 a constitutional mutation (C-->T substitution leading to a stop codon) in the MSH2 gene was identified. We conclude that the diagnosis of MTS, which is mainly clinical, should take into account an ample phenotypic variability, which includes both cases with typical cancer aggregation in families and cases characterized by the association of visceral malignancies with multiple keratoacanthomas (without sebaceous lesions), without an apparent family history of cancer.

Adenocarcinoma↗
PubMed2005

Attenuated familial adenomatous polyposis and Muir-Torre syndrome linked to compound biallelic constitutional MYH gene mutations.

Attenuated familial adenomatous polyposis and Muir-Torre syndrome linked to compound biallelic constitutional MYH gene mutations.Peculiar dermatologic manifestations are present in several heritable gastrointestinal disorders. Muir-Torre syndrome (MTS) is a genodermatosis whose peculiar feature is the presence of sebaceous gland tumors associated with visceral malignancies. We describe one patient in whom multiple sebaceous gland tumors were associated with early onset colon and thyroid cancers and attenuated polyposis coli. Her family history was positive for colonic adenomas. She had a daughter presenting with yellow papules in the forehead region developed in the late infancy. Skin and visceral neoplasms were tested for microsatellite instability and immunohistochemical status of mismatch repair (MMR), APC and MYH proteins. The proband colon and skin tumors were microsatellite stable and showed normal expression of MMR proteins. Cytoplasmic expression of MYH protein was revealed in colonic cancer cells. Compound heterozygosity due to biallelic mutations in MYH, R168H and 379delC, was identified in the proband. The 11-year-old daughter was carrier of the monoallelic constitutional mutation 379delC in the MYH gene; in the sister, the R168H MYH gene mutation was detected. This report presents an interesting case of association between MYH-associated polyposis and sebaceous gland tumors. These findings suggest that patients with MTS phenotype that include colonic polyposis should be screened for MYH gene mutations.

Adenomatous Polyposis Coli↗
PubMed2004

Genetic testing among high-risk individuals in families with hereditary nonpolyposis colorectal cancer.

Hereditary nonpolyposis colorectal cancer (HNPCC) is frequently associated with constitutional mutations in a class of genes involved in DNA mismatch repair. We identified 32 kindreds, with germline mutations in one of three genes hMSH2, hMLH1 or hMSH6. In this study, we purposed to evaluate how many high-risk individuals in each family underwent genetic testing: moreover, we assessed how many mutation-positive unaffected individuals accepted colonoscopic surveillance and the main findings of the recommended follow-up. Families were identified through a population-based registry, or referred from other centres. Members of the families were invited for an education session with two members of the staff. When a kindred was consistent with HNPCC, neoplastic tissues were examined for microsatellite instability (MSI) and immunohistochemical expression of MSH2, MLH1 and MSH6 proteins. Moreover, constitutional mutations were searched by SSCP or direct sequencing of the whole genomic region. Of the 164 subjects assessed by genetic testing, 89 were gene carriers (66 affected - that is, with HNPCC-related cancer diagnosis - and 23 unaffected) and 75 tested negative. Among the 23 unaffected gene carriers, 18 (78.3%) underwent colonoscopy and four declined. On a total of 292 first degree at risk of cancer, 194 (66.4%) did not undergo genetic testing. The main reasons for this were: (a) difficulty to reach family members at risk, (b) lack of collaboration, (c) lack of interest in preventive medicine or 'fatalistic' attitude towards cancer occurrence. The number of colorectal lesions detected at endoscopy in gene carriers was significantly (P<0.01) higher than in controls (noncarriers). We conclude that a large fraction of high-risk individuals in mutation-positive HNPCC families does not undergo genetic testing, despite the benefits of molecular screening and endoscopic surveillance. This clearly indicates that there are still barriers to genetic testing in HNPCC, and that we are unable to provide adequate protection against cancer development in these families.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Trend of incidence, subsite distribution and staging of colorectal neoplasms in the 15-year experience of a specialised cancer registry.

BACKGROUND: Two-thirds of colorectal malignancies are localised in the left colon and rectum. Recent studies suggest a trend towards an increase of right-sided tumours which might have important implications for screening and surveillance. A colorectal cancer registry was set up in Modena, northern Italy, with the purpose of examining incidence, subsite distribution and staging of colorectal malignancies over a 15-year period. PATIENTS AND METHODS: From 1984 to 1998, 2517 tumours in 2462 patients were detected and staged with the tumour node metastasis (TNM) system. The 'right colon' was considered from caecum to splenic flexure; the 'left colon' included descending and sigmoid colon; and the 'rectum' included rectosigmoid junction, ampulla and anus. RESULTS: Cancer incidence showed an overall increase. Considering the various subsites, an increase of 33.7% in all colonic segments was shown whereas rectal tumours tended to decline. TNM staging showed a gradual increase of localised lesions (41.2% in 1984 versus 53.3% in 1998), with a proportional reduction of advanced tumours. CONCLUSIONS: Our study indicates an increase of tumour incidence in all colonic segments more than a shift to the right colon. TNM staging tended to improve with an appreciable increase of localised lesions. These findings could be consequent to a more extensive use of colonoscopy.

Aged↗
PubMed2004

Aetiology of colorectal cancer and relevance of monogenic inheritance.

BACKGROUND AND AIMS: Although diet and lifestyle are associated with the development of colorectal malignancies, the only clearly identified aetiological factors in colorectal cancer are inheritance (hereditary non-polyposis colorectal cancer (HNPCC) and familial polyposis), inflammatory bowel diseases, papillomavirus, and acquired immunodeficiency syndrome (AIDS). Our aim was to determine what proportion of colorectal neoplasms could be attributed to these specific factors. PATIENTS AND METHODS: Data from a colorectal cancer registry were analysed over a 15 year period, during which nearly 2500 cases were recorded. In patients with suspected HNPCC, microsatellite instability and immunohistochemical expression of proteins encoded by the main DNA mismatch repair genes were assessed. In families with unstable neoplasms, constitutional mutations of the mismatch repair genes hMSH2, hMLH1, and hMSH6 were evaluated by single strand conformation polymorphism analysis and sequencing. RESULTS: Inflammatory bowel diseases, familial polyposis, and AIDS were rare causes of colorectal cancer (three, three, and one case, respectively). Anal squamous carcinoma developed in 27 patients (1.0%) and could be attributed to papillomavirus infection. In 58 patients (from 34 families) a clinical diagnosis of HNPCC was established (2.4%). In total, cases with a known aetiology were 92 (3.7% of all patients). Microsatellite instability was detected in 15 cancers from HNPCC families, and germline mutations in six families (12 patients, 0.5% of the total). Families with unstable tumours, with or without mutations, were clinically similar, suggesting the involvement of the mismatch repair system even when mutations were not detected. CONCLUSIONS: The study suggests that the aetiology of colorectal malignancies remains elusive in the large majority of cases. Among specific causes, HNPCC represents the most frequent. However, with a population based approach, constitutional mutations of the main genes involved in HNPCC can be detected in only 20% of cases.

Acquired Immunodeficiency Syndrome↗
PubMed2003

The carnitine system and body composition.

Carnitine is a trimethylamine molecule that plays a unique role in cell energy metabolism. Mitochondrial betaoxidation of long-chain fatty acids, the major process by which fatty acids are oxidized, is ubiquitously dependent on carnitine. Control of mitochondrial beta-oxidation through carnitine adapts to differing requirements in different tissues. The physiological role of carnitine and its system in body composition is understood from insights into skeletal muscle metabolism, which converge into the metabolic heterogeneity of muscle fibers, and contractile properties that are correlated with phenotypes of resistance to fatigue. In skeletal muscle, the importance of the function of the carnitine system in the control and regulation of fuel partitioning not only relates to the metabolism of fatty acids and the capacity for fatty acid utilization, but also to systemic fat balance and insulin resistance. The carnitine system is shown to be determinant in insulin regulation of fat and glucose metabolic rate in skeletal muscle, this being critical in determining body composition and relevant raised levels of risk factors for cardiovascular disease, obesity, hypertension, and type 2 diabetes.

Animals↗
PubMed2001

The role of hPMS1 and hPMS2 in predisposing to colorectal cancer.

Hereditary nonpolyposis colorectal cancer (HNPCC) is attributable to a deficiency of mismatch repair. Inactivation of DNA mismatch repair underlies the genesis of microsatellite instability in colorectal cancer. Germline mutations in three DNA mismatch repair genes, hMSH2, hMLH1, and hMSH6, have been found to segregate in HNPCC and HNPCC-like families. The two DNA mismatch repair genes hPMS1 and hPMS2 have also been suggested to predispose to HNPCC. In this study, 84 HNPCC and HNPCC-like kindreds without known mutations in the other three known DNA mismatch repair genes were screened for germline mutations in the hPMS1 or hPMS2 gene. No clear-cut pathogenic mutations were identified. Conversion technology was used to detect a large hMSH2 deletion in two affected members of the kindred in which the hPMS1 mutation was originally reported, whereas the hPMS1 mutation was only present in one of these two individuals. Since the hPMS1 and hPMS2 genes were first reported, germline mutations in hPMS2 have been demonstrated primarily in patients with Turcot's syndrome. However, no mutation in any of the two genes has been found to segregate in HNPCC families. Until there is better evidence for an increased colorectal cancer risk associated with germline mutations in these genes, a conservative interpretation of the role of mutations in these genes is advised.

Adenosine Triphosphatases↗
PubMed2001

Molecular screening for hereditary nonpolyposis colorectal cancer: a prospective, population-based study.

PURPOSE: Germline mutations in mismatch repair genes predispose to hereditary nonpolyposis colorectal cancer (HNPCC). To address effective screening programs, the true incidence of the disease must be known. Previous clinical investigations reported estimates ranging between 0.5% and 13% of all the colorectal cancer (CRC) cases, whereas biomolecular studies in Finland found an incidence of 2% to 2.7% of mutation carriers for the disease. The aim of the present report is to establish the frequency of the disease in a high-incidence area for colon cancer. PATIENTS AND METHODS: Through the data of the local CRC registry, we prospectively collected all cases of CRC from January 1, 1996, through December 31, 1997 (N = 391). Three hundred thirty-six CRC cases (85.9% of the incident cases) were screened for microsatellite instability (MSI) with six to 12 mono- and dinucleotide markers. MSI cases were subjected to MSH2 and MLH1 germline mutation analysis and immunohistochemistry; the methylation of the promoter region was studied for MLH1. RESULTS: Twenty-eight cases (8.3% of the total) showed MSI. MSI cases differed significantly from microsatellite-stable (MSS) cases for their proximal location (P <.01), high mucinous component (P <.01), and poor differentiation (P =.002). Of MSI cases studied (n = 12), only one with a family history compatible with HNPCC had a germline mutation (in MSH2). Five other patients with a family history of HNPCC (two with MSI and three with MSS tumors) did not show germline mutations. CONCLUSION: We conclude that the incidence of molecularly confirmed HNPCC (one [0.3%] of 336) in a high-incidence area for CRC is lower than in previous biomolecular and clinical estimates.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Clinical and biologic heterogeneity of hereditary nonpolyposis colorectal cancer.

MMR gene mutations and MSI are not found in all clinically diagnosed HNPCC families. We evaluated whether MMR genotyping and tumor MSI analysis could identify distinct clinical subgroups among HNPCC families. Twenty-nine clinical HNPCC families were divided into 3 groups: A, families with hMLH1 or hMSH2 gene mutations; B, MMR gene mutations not present but MSI present in at least 50% of tumors tested; C, mutational and MSI analyses negative. We evaluated tumor spectrum, age at onset, risk of cancer in the follow-up and survival for CRC in the 3 groups. Tumors of the target organs in HNPCC (colon and rectum, endometrium, ovary, small bowel, stomach, renal pelvis and ureter) were more frequent in the first 2 groups than in the latter. Colon cancer was more frequently located in the proximal colon and showed an earlier age at onset in families with MMR gene mutation or with MSI than in families with stable tumors. Comparing the occurrence of tumors in the follow-up, in the first 2 groups patients younger than 50 years had a higher RR, which was particularly marked for CRC (RR = 18.6 for group A vs. group C, RR = 16.7 for group B vs. group C). CRC patients in the first 2 groups had a better clinical prognosis. The results of molecular analysis could distinguish, within clinically defined HNPCC families, different subgroups to which specific programs of surveillance could be addressed.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Microsatellite instability and mismatch-repair protein expression in hereditary and sporadic colorectal carcinogenesis.

Aberrant crypt foci (ACF) are microscopic clusters of altered colonic crypts considered premalignant lesions in the large bowel. Genomic instability at short tandem repeats in the DNA, referred to as microsatellite instability (MSI) is the hallmark of hereditary nonpolyposis colorectal carcinoma (HNPCC) caused by mutations in DNA mismatch-repair genes, mostly hMLH1 and hMSH2. In this study, we evaluated for MSI ACF (n = 16), adenomas (n = 18), carcinomas (n =22), and lymph node metastases (n = 3) from 17 patients with colorectal cancer positive for MSI. Ten patients were members of HNPCC families; 7 patients had no family history of cancer. MSI was found in 7 of 7 (100%) ACF and 11 of 12 (91%) adenomas from patients with HNPCC. MSI was not related to histology and size of ACF. A progressive increase in instability as estimated by the number of shifted bands was observed along the ACF-adenoma-carcinoma sequence. In contrast, two of nine (22%) ACF and none of six adenomas from patients with MSI sporadic carcinoma were unstable at microsatellite loci. hMLH1 or hMSH2 protein expression was altered only in MSI-positive premalignant lesions (ACF and/or adenomas), but not in all MSI-positive lesions in patients with HNPCC. These observations provide evidence of the premalignant nature of ACF in HNPCC and suggest that MSI is a very early event both in HNPCC and in sporadic colorectal carcinogenesis, although in the latter it seems infrequent.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Methylation pattern of different regions of the MLH1 promoter and silencing of gene expression in hereditary and sporadic colorectal cancer.

Nonrandom, widespread promoter methylation of tumor suppressor genes is a common mechanism of gene inactivation during tumorigenesis. We examined the methylation status of two distinct regions of the MLH1 promoter (proximal and distal to the transcription start site) and the MLH1 gene expression by methylation-specific PCR and immunohistochemistry. A total of 72 colorectal tumors, both with (n = 51, 22 affected by hereditary nonpolyposis colorectal cancer, HNPCC, defined according to the international clinical criteria and 29 sporadic cases) and without microsatellite instability (MSI) (n = 21) were studied. Methylation was present in at least one of the two promoter regions in 86% of the sporadic MSI cases, in 33% of the cases lacking MSI, and in 23% of the HNPCC tumors. In the HNPCC cases with a known MLH1 mutation (n = 10) none of the two promoter regions was methylated. Hypermethylation in both MLH1 promoter regions was seen in 45% of the MSI sporadic cases vs. 5% of the MSI-negative cases and 0% of the HNPCC cases. The overall concordance between the two promoter regions regarding methylation status was good (P = 0.009), but no significant correlation between methylation and suppression of the MLH1 immunohistochemical expression was found. Our data confirm that mutation and hypermethylation are mutually exclusive mechanisms in inducing mismatch repair deficiency and support the hypothesis of methylation as a process evenly distributed along the different regions of the promoter.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Phenotype-genotype correlations in an extended family with adenomatosis coli and an unusual APC gene mutation.

PURPOSE: Genotype-phenotype correlations in familial adenomatous polyposis are only partially understood and, in particular, little is known about the biomolecular characteristics of desmoid tumors, which are one of the most serious and frequent manifestations of familial adenomatous polyposis. In the present study, we describe a family with familial adenomatous polyposis, with peculiar clinical characteristics (i.e., frequency and severity of desmoid neoplasms) associated with an unusual mutation of the adenomatosis polyposis coli gene. If confirmed by other investigations, these findings might help to understand the biologic mechanisms by which specific adenomatosis polyposis coli mutations predispose to desmoid tumors. METHODS: The family with familial adenomatous polyposis, living in southern Italy, was studied from 1985 to the end of 1999; at this date, 15 individuals have been affected by histologically verified familial adenomatous polyposis, 11 of whom had desmoid tumors. A total of 19 family members were studied for adenomatosis polyposis coli gene mutations; 13 of them tested positive and 6 negative. The analytical procedure-previously described-consisted of the extraction of peripheral blood cell DNA, amplification of exon 15 by polymerase chain reaction, single-strand conformation polymorphism analysis, and direct sequencing of the DNA fragment containing the mutation. RESULTS: The main clinical features of the family were 1) a high frequency of desmoid tumors and, consequently, a high penetrance of the desmoid trait in all branches of the family and in 11 (73.3 percent) of 15 affected individuals and 2) severity of desmoids in at least 4 family members, 2 of whom died for causes related to the presence of these tumors. The molecular basis of the disease was an uncommon mutation of the adenomatosis polyposis coli gene, consisting of a large deletion of 310 base pairs at codon 1,464, with duplication of the breakpoint (4,394ins15del310), leading to a stop codon at position 1,575. CONCLUSIONS: The present study shows that a truncating mutation in the adenomatosis polyposis coli gene at the beginning of the region frequently associated with desmoids induced a familial adenomatous polyposis phenotype featured by a high penetrance of the desmoid trait, with severe disease in several affected members of both sexes. The study may help to understand the biologic mechanisms of genotype-phenotype correlations in adenomatosis coli.

Adenomatous Polyposis Coli↗
PubMed2000

Carnitine: an osmolyte that plays a metabolic role.

Carnitine, gamma-trimethyl-beta-hydroxybutyrobetaine, is a small molecule widely present in all cells from prokaryotic to eukaryotic ones. It is the sole source of carbon and nitrogen in some bacteria; it serves as osmoprotectant in others. It is a carrier of acyl moieties, and exclusively of long-chain fatty acids for mitochondrial beta-oxidation in mammals. The conspicuously similar composition of the intracellular milieu among widely different species in relation to organic osmolyte systems involves the methylamine family to which carnitine belongs. This prompted us to examine the osmolytic properties of carnitine in an attempt to clarify the metabolic functions carnitine has acquired during evolution. An understanding of the metabolic functions of this organic compatible solute impinge on research involving this compound.

Animals↗
PubMed2000

Cancer and anticancer therapy-induced modifications on metabolism mediated by carnitine system.

An efficient regulation of fuel metabolism in response to internal and environmental stimuli is a vital task that requires an intact carnitine system. The carnitine system, comprehensive of carnitine, its derivatives, and proteins involved in its transformation and transport, is indispensable for glucose and lipid metabolism in cells. Two major functions have been identified for the carnitine system: (1) to facilitate entry of long-chain fatty acids into mitochondria for their utilization in energy-generating processes; (2) to facilitate removal from mitochondria of short-chain and medium-chain fatty acids that accumulate as a result of normal and abnormal metabolism. In cancer patients, abnormalities of tumor tissue as well as nontumor tissue metabolism have been observed. Such abnormalities are supposed to contribute to deterioration of clinical status of patients, or might induce cancerogenesis by themselves. The carnitine system appears abnormally expressed both in tumor tissue, in such a way as to greatly reduce fatty acid beta-oxidation, and in nontumor tissue. In this view, the study of the carnitine system represents a tool to understand the molecular basis underlying the metabolism in normal and cancer cells. Some important anticancer drugs contribute to dysfunction of the carnitine system in nontumor tissues, which is reversed by carnitine treatment, without affecting anticancer therapeutic efficacy. In conclusion, a more complex approach to mechanisms that underlie tumor growth, which takes into account the altered metabolic pathways in cancer disease, could represent a challenge for the future of cancer research.

Antineoplastic Agents↗
PubMed2000

Staging and survival of colorectal cancer: are we making progress? The 14-year experience of a Specialized cancer Registry.

BACKGROUND AND AIMS: It is still unclear whether recent advancements in colorectal cancer research have led to an improvement in management and prognosis of the disease. Through the data of a specialized colorectal cancer Registry we aimed at analysing pathological staging and 5-year survival of all patients with malignancies of large bowel diagnosed between 1984 and 1997. Main objective was to ascertain whether or not we are making progress in the control of this common neoplasm. PATIENTS AND METHODS: During the 14-year period 1984-97, a total of 2,240 colorectal cancer patients were registered, for a crude incidence rate of 64.5 and 55.2/100,000/year in males and females, respectively Tumours were staged with "Tumour, Node, Metastasis" system, corresponding to Dukes' classification, into four main groups. Survival was assessed with Life Table analysis, and statistical significance--between various subgroups--evaluated with Log-Rank Test. RESULTS: Crude incidence rates of colorectal neoplasms showed minor fluctuations during initial period of registration, increasing sharply after 1990 mainly due to localized (stage I and II) lesions and, to a lesser degree, to stage III tumours. Number of advanced (stage IV and unstaged) malignancies remained virtually stable. When results were expressed as percent of total cases, the fraction of localized lesions increased from 39% in the biennium 1984-5 to 51.6% in 1986-97, and the proportion of advanced tumours fell from 39% to 21.6% (p for trend <0.001). As expected, 5-year survival was significantly (p<0.002) more favourable for individuals diagnosed in 1990-91 than for patients registered in 1984-89. CONCLUSIONS: In Northern Italy, incidence rates of colorectal carcinoma are rising. This trend is associated with a sharp increase of newly detected localized lesions and with a significant improvement of overall 5-year survival. The result may be attributed to several concomitant factors, such as: A] wider use of colonoscopy, B) increased education of patients, C) more attention given to symptoms.

Adult↗
PubMed2000

Aberrant crypt foci in colorectal carcinogenesis. Cell and crypt dynamics.

Aberrant crypt foci (ACF) have been identified on the colonic mucosal surface of rodents treated with colon carcinogens and of humans after methylene-blue staining and observation under a light microscope. Several lines of evidence strongly suggest that ACF with certain morphological, histological, cell kinetics, and genetic features are precursor lesions of colon cancer both in rodents and in humans. Thus, ACF represent the earliest step in colorectal carcinogenesis. This paper has the main purpose of reviewing the evidence supporting this view, with particular emphasis on cell and crypt dynamics in ACF. ACF have been used as intermediate biomarkers of cancer development in animal studies aimed at the identification of colon carcinogens and chemopreventive agents. Recently, evidence has also shown that ACF can be effectively employed in chemopreventive studies also in humans.

Animals↗